High TNFAIP6 level is associated with poor prognosis of urothelial carcinomas

[[abstract]]Purpose: Inflammatory responses affect each stage of carcinogenesis, from initiation, through invasion, to metastasis. Studies have shown that chronic inflammation induced by environmental and occupational exposures increase the risk of developing urothelial carcinoma (UC). Using a published UC transcriptome (GSE32894), we identified that among genes associated with inflammatory response (GO:0006954), TNFAIP6 was significantly upregulated during UC progression. Therefore, we investigated the association of TNFAIP6 with disease features, metastasis and survival in our well-characterized cohort of UC. Methods: We determined TNFAIP6 expression in 340 upper urinary tract UCs (UTUC) and 295 urinary bladder UCs (UBUC) using immunohistochemistry and evaluated the results using H-score. TNFAIP6 expression correlated with clinicopathological features, disease-specific survival, and metastasis-free survival. Survival analysis was performed using Kaplan–Meier curves and Cox proportional hazards model. Results: High TNFAIP6 expression was significantly associated with advanced pathological stage, lymph node metastasis, perineural invasion, vascular invasion, and high mitotic activity. Multivariate analysis identified high TNFAIP6 expression as an independent predictor of disease-specific survival (hazard ratio in UTUC: 2.891, P = 0.003; in UBUC: 2.175, P = 0.017) and metastasis-free survival (hazard ratio in UTUC: 3.803, P < 0.001; in UBUC: 3.845, P < 0.001). Conclusion: High TNFAIP6 expression is associated with aggressive clinicopathological features and poor prognosis in UCs, suggesting it may serve as a novel prognosticator and treatment target. TNFAIP6 immunostaining may be used with current pathological examinations for better risk stratification for UCs